This invention relates to agglomerates of xcex2-lactam antibiotics, including e.g. penicillin V potassium, amoxicillin trihydrate, cephalexin monohydrate, which are suitable for direct tablet formation.
The most important and most frequently used form for orally administrable xcex2-lactam antibiotics and mixtures, containing xcex2-lactam antibiotics beside a second pharmaceutically active agent and optionally beside auxiliaries, is a tablet or a film tablet. For the production of a tablet or a film tablet, there are at the moment two processes known, namely granulation and direct tablet formation.
During granulation, generally very fine-grained, powdered, cohesive, non free-flowing and non-compressible pharmaceutically active agents are granulated in a multi-stage process to form coarser, free-flowing and compressible granules. In such a process, the pharmaceutically active agents are mixed in a first step with a binding agent, compacted whilst moist or dry and subsequently granulated in a second step through a sieve. The binding agent may, e.g. be dissolved in the moistening liquid used for moistening and granulating the powder. In a moist granulation process, drying of the granules is carried out including subsequent sieving to the final grain size. In a dry granulation process, after granulation it is generally necessary to separate the particles which are too coarse or too fine, and to recycle these particles, the coarse grain particles being pulverized again and the fine particles being compacted again. The granulates obtained may be mixed with auxiliaries which are preferably pharmaceutically acceptable required for tablet formation and compressed into tablets.
Granulation is generally very time and energy consuming and expensive, and may be thus extremely uneconomical. The described production processes for a tablet requires a considerable amount of apparatus and a high amount of validation work, and owing to the large number of production steps there are many sources of error.
Direct tablet formation is a much easier process; the pharmaceutically active agents being easily mixed with auxiliaries (carriers, binding agents, lubricants etc.) and the mixture is pressed into tablets. However, until now, despite the clear economic advantages over granulation, direct tablet formation could only be used to a limited extent, since it may generally only be carried out with, e.g. the following provisos: The pharmaceutically active agents has to be sufficiently free-flowing and compressible per se, and the proportion of pharmaceutically active agents per tablet must be a maximum of 100 mg or 25%. With such provisos good free-flow capability and good compressibility may only be obtained by addition of high amounts of special auxiliaries (e.g. Tablettose(copyright), Ludipress(copyright) etc.).
In the case of xcex2-lactam antibiotic tablets, the proportion of the xcex2-lactam antibiotic per tablet may be up to 80% and more (e.g. 1 g and more), and xcex2-lactam antibiotics are generally not sufficiently free-flowing and compressible per se. For example, especially penicillin V potassium, phenoxymethylpenicillin potassium, amoxicillin trihydrate and cephalexin monohydrate are generally obtained during production in an average volume-based grain size of 10 xcexcm to 30 xcexcm with the following grain size distribution:
and having a bulk density of 0.15 g/ml to 0.45 g/ml.
These characteristics make it generally impossible to use the direct tablet formation process for xcex2-lactam antibiotics.
Mixtures containing xcex2-lactam antibiotics, for example a combination of amoxycillin trihydrate (xcex2-lactam antibiotic) as, e.g. an anti-bacterially active compound with a second pharmaceutically active agent, e.g. a potassium salt of clavulanic acid (potassium clavulanate) as, e.g. a xcex2-lactamase inhibitor are of enormous interest for the treatment of infections caused by gram-positive and gram-negative bacteria, which have become resistant to amoxycillin as a result of xcex2-lactamase formation. Combinations of amoxicillin trihydrate/potassium clavulanate/auxiliaries are on the market under the trade name Augmentin(copyright). The most important pharmaceutical form for the oral administration thereof is a tablet or a film tablet. Up to now, the preparation of Augmentin(copyright) tablets or film tablets has been particularly difficult because of the following problems in addition to the problems with tablet formation in case of xcex2-lactam antibiotics as described above:
A potassium clavulanate may be extremely moisture sensitive and may degrade quickly in the presence of water
A mixture of two pharmaceutically active agents in a defined ratio has to be produced which may include the danger of disintegration of the two components during production because, e.g. of inhomogeneous contents of a pharmaceutically active agent in a tablet or a film tablet
The total proportion of the two pharmaceutically active agents per tablet may be up to 80% and more and the ability of the active ingredients to be compressed into a tablet or a film tablet may be determined almost exclusively by the physical properties of the active ingredients, i.e. deformation behaviour under pressure.
Thus, when producing a tablet or a film tablet with a combination of amoxicillin trihydrate and potassium clavulanate in a first step granulation has generally to be carried out, in order to ensure that a compressable mixture with satisfactory free-flow capability and compressibility is obtained; and to prevent disintegration of the active ingredients. However, owing to the extreme sensitivity of potassium clavulanate towards moisture, moist granulation with aqueous-alcoholic mixtures or binding agent solutions; or with pure water; which is at present the usual way for the production of xcex2-lactam antibiotic tablets or film tablets, cannot be effected; because during moistening and subsequent granulation of the amoxycillin trihydrate/potassium clavulanate/auxiliaries powder, as well as during the subsequent drying of the granules, potassium clavulanate may be degraded due to the water present to an unacceptable extent.
In practice, up to now for the production of tablets or film tablets containing amoxycillin trihydrate and potassium clavulanate with sufficient uniformity there are in general only two alternative granulation processe, both of which may be complicated, and extremely uneconomical and unecological, namely:
Moist Granulation With Water-free Organic Solvents
The active ingredients amoxycillin trihydrate and potassium clavulanate are mixed in a first step with a binding agent, the mixture is moistened with a water-free, organic solvent, granulated and dried. The binding agent may also be added dissolved in the solvent. The granulates obtained may be sieved to the final grain size and mixed with tablet forming auxiliaries (binding agents, disintegrants etc.) before being compressed into tablets. Such a process is uneconomical and unecological, since the solvent has to be recycled; special equipment is necessary, solvent losses arise, etc.
Dry Granulation (Compactation, Briquette Formation)
The active ingredients amoxycillin trihydrate and potassium clavulanate may generally be mixed with a binding agent and compacted in dry form. Compactation may take place by compressing the pharmaceutically active agent/binding agent-mixture either on a roller compactor to form so-called xe2x80x9cshellsxe2x80x9d or on a tablet press having large stamps to form so-called xe2x80x9cbriquettesxe2x80x9d. Both the shells and the briquettes obtained are pulverized or broken in a mill or a sieve, in order to obtain an appropriate granulate. After granulation it is generally necessary to separate the particles which are too coarse or too fine, and to recycle these particles, the coarse grain particles being pulverized again and the fine particles being compacted again (briquette formation). The granulates thus obtained may be mixed with auxiliaries required for tablet formation (lubricants, disintegrants etc.) which are preferably pharmaceutically acceptable and the mixture may be compressed to form tablets. Parts of the lubricants or disintegrants may be incorporated (mixed with active ingredient) prior to compacting/briquette formation.
Such a dry granulation production process may be unfavourable because
it is very time-consuming
it is expensive
losses of active ingredient may be practically unavoidable
it may require a considerable number of apparatus
a high amount of pre-validation work is necessary
a large number of production steps may be necessary
there are a considerable amount of error sources.
Despite of such disadvantages, such a process is to be used for the production of amoxycillin trihydrate/potassium clavulanate film tablets owing obviously to the absence of alternative possibilities (see e.g. PCT application WO 95/28927).
We have surprisingly found agglomerates of xcex2-lactams, including penicillin V potassium, amoxicillin trihydrate, cephalexin monohydrate which are free from auxiliaries and which have an excellent flowability, and which may be compressed directly into tablets optionally after mixing these agglomerates with auxiliaries; and a process for the production of free-flowing and auxiliary-free compressible xcex2-lactam antibiotic agglomerates from powders.
We have also surprisingly found a mixture of pharmaceutically active agents including at least one xcex2-lactam antibiotic, such as a mixture of amoxycillin trihydrate and potassium clavulanate, containing optionally auxiliaries, suitable for the production of a tablet (or a film tablet) by direct tablet formation; and a process for direct tablet formation of a mixture of pharmaceutically active agents including at least one xcex2-lactam antibiotic, such as a mixture of amoxycillin trihydrate and potassium clavulanate, containing optionally auxiliaries which are pharmaceutically acceptable, avoiding moisturing of the mixture in fewer production steps than according to prior art processes.
Auxiliary-free agglomerates of a xcex2-lactam antibiotic are new and forms part of the present invention.
Auxiliary-free agglomerates of a xcex2-lactam antibiotic which have an excellent flowability, and which may be compressed directly into tablets optionally after mixing with auxiliaries may be e.g. such, of an average volume-based grain size of 200 xcexcm to 1000 xcexcm, preferably 400 xcexcm to 600 xcexcm. The distribution of grain size may be as follows:
The bulk density of the agglomerates may, for example, be in the range of about 0.4 g/ml to about 0.8 g/ml, e.g. 0.4 g/ml to 0.8 g/ml; such as about 0.5 g/ml to about 0.7 g/ml, e.g. 0.5 g/ml to 0.7 g/ml.
The present invention provides therefore in one aspect auxiliary-free agglomerates of xcex2-lactam antibiotics; especially of penicillin V potassium, amoxicillin trihydrate and cephalexin monohydrate; having for example an average volume-based grain size of 100 xcexcm to 1000 xcexcm, preferably 400 xcexcm to 600 xcexcm, such as 200 m to 600 xcexcm; having for example the following distribution of grain size:
and/or having a bulk density of 0.4 g/ml to 0.8 g/ml, for example 0.5 g/ml to 0.7 g/ml.
Auxiliary-free agglomerates according to the invention may be produced as follows: A solid xcex2-lactam antibiotic, e.g. penicillin V potassium, amoxicillin trihydrate and cephalexin monohydrate, e.g. in form of a powder, with an average volume-based grain size of 10 xcexcm to 30 xcexcm, with about the following distribution of grain size:
and a bulk density of 0.15 g/ml to 0.45 g/ml, as usually obtained in the production process for a xcex2-lactam antibiotic, may be formed into a paste, for example by conventional methods, with a liquid in which the xcex2-lactam antibiotic is insoluble or slightly soluble. This paste may be kneaded and extruded in a double-screwed extruder having a specific mechanical energy input of 0.01 to 0.1 kilowatt-hour/kg, preferably of 0.02 to 0.6 kilowatt-hour/kg.
During the kneading procedure the temperature of the paste may be maintained in a range of about 10xc2x0 C. to about 80xc2x0 C., e.g. 10xc2x0 C. to 80xc2x0 C. Auxiliary-free agglomerates may be obtained which may be dried, e.g. as conventional, for example in a fluidized bed drier.
In another aspect the present invention provides a process for the production of auxiliary-free agglomerates of a xcex2-lactam antibiotic, by the following steps
a) forming a paste from a xcex2-lactam antibiotic with a liquid,
b) kneading the paste at a temperature of 10xc2x0 C. to 80xc2x0 C.,
c) extruding the paste in a double-screwed extruder having for example a specific mechanical energy input of 0.01 to 0.1 kilowatt-hour/kg, and, if desired,
d) drying the agglomerates obtained.
The xcex2-lactam, e.g. in form of a powder, may be placed into the extruder in an already moist form, or in dry form. If the xcex2-lactam antibiotic, for example in form of a powder, is placed into the extruder in dry form the liquid may be dispersed into the extruder simultaneously with the xcex2-lactam antibiotic.
Appropriate liquids include e.g. water, alcohols and mixtures thereof; as well as organic solvents such as acetone. An alcohol may preferably be ethanol or isopropanol.
The amount of liquids may be appropriate to result in a kneadable paste with the xcex2-lactam antibiotic and may be preferably as follows (expressed in % by weight, based on the paste):
about 3 to about 20, e.g. 3 to 20, preferably about 5 to about 10, e.g. 5 to 10 for the case that the active ingredient is slightly dissolved by the liquid; and about 5 to about 35, e.g. 5 to 35, preferably about 10 to about 20, e.g. 10 to 20 for the case that the active ingredient is insoluble in the liquid.
The optimum degree of density of the xcex2-lactam antibiotic agglomerates may be such that mechanical stability of the agglomerates is appropriate, i.e. after drying, the agglomerates should not disintegrate into a powder because this would negatively affect the free-flow capability. But the agglomerates should not be extremely mechanical stable (density too high), because during the tablet formation process such extreme stable agglomerates would not be prone to form mechanically stable tablets which thus could not be produced.
Surprisingly, the optimum degree of density in a process according to the present invention corresponds exactly to the observed maximum torque pick-up on the extrusion screw which passes through during extrusion as the amount of liquid increases. Thus, the optimum degree of density of the powder is very easily controllable.
The xcex2-lactam agglomerates according to the present invention may be compressed, optionally after mixing with auxiliaries which are preferably pharmaceutically acceptable, such as polyvinyl pyrrolidone, talcum, magnesium stearate; directly into tablets of high unit weight, satisfactory mechanical stability and rapid release of of the xcex2-lactam antibiotic (active ingredient). Since no binding agent and no bindings between the particles of active ingredient and a binding agent are generally present in the agglomerates as are generally present in moist granulation processes, the release of active ingredient from the directly compressed tablets according to the present invention may be considerably faster than from tablets produced by granulation as usual.
Compared with tablets produced by the multi-stage moist granulation process as described above , the tablets produced according to the present invention by direct tablet formation of the new-type agglomerates of active ingredient have, e.g. the following advantages:
Owing to the excellent free-flow capability of the agglomerates according to the present invention, the weight deviation of the tablets is less. The optimum degree of density of the agglomerates results in high mechanical stability (higher degree of hardness, lower friability), and, despite of this, the release of the pharmaceutically active agent, i.e. of the xcex2-lactam antibiotic, from the tablet is considerably quicker.
A mixture of a xcex2-lactam antibiotic such as amoxicillin trihydrate with a second pharmaceutically active agent, e.g. potassium clavulanate, may easily be produced by mixing agglomerates of a xcex2-lactam antibiotic, e.g. of amoxicillin trihydrate, which are sufficiently free-flowing and compressible, such as agglomerates obtainable by the process of the present invention, with a second pharmaceutically active agent, which may be generally insufficiently free-flowing and incompressible, such as, e.g. potassium clavulanate having for example a grain size of ca. 5 xcexcm to 100 xcexcm which may be a normal grain size in pharmaceutical powders, obtained during production. We have surprisingly found that the mixture is sufficiently free-flowing and compressible for direct tablet formation even if a high degree of potassium clavulanate is mixed with the xcex2-lactam antibiotic agglomerates according to the present invention.
The weight ratio of agglomerats of a xcex2-lactam antibiotic, such as amoxycillin trihydrate and potassium clavulanate in the directly compressable mixture may be in the range of 12:1 to 1:1; e.g. 7:1 to 1:1; such as 4:1 to 1:1; for example 2:1 to 1:1.
Mixing of the xcex2-lactam antibiotic agglomerates with a second pharmaceutically active agent, e.g. potassium clavulanate, e.g. in form of a powder, may be effected, e.g. in a forced-flow or free-fall mixer. Agglomerates of a xcex2-lactam antibiotic according to the present invention, e.g. agglomerates of amoxycillin trihydrate may function as a carrier for for the second pharmaceuticalle active agent, e.g. potassium clavulanate, e.g. in form of a powder.
Auxiliaries, which are preferably pharmaceutically acceptable, for example auxiliaries conventional in tablet formation processes, such as for example lubricants, e.g. magnesium stearate; mold-separating agents, e.g. talcum; binding or filling agents, e.g. polyvinyl pyrrolidone, micro-crystalline cellulose (Avicel), modified starch (Starch 1500 J); disintegrating agents, e.g. crosslinked carboxymethyl cellulose (Acxe2x80x94Dixe2x80x94Sol), crosslinked carboxymethyl starch (Primojel) or crosslinked polyvinyl pyrrolidone (PVPP); may be present in the mixture of xcex2-lactam antibiotic agglomerates and potassium clavulanate powder, preferably in small amounts because it was found that only small amounts may be necessary. Auxiliaries, optionally pre-dried, may be mixed into the mixture, for example before, during or after mixing of the xcex2-lactam antibiotic agglomerates with potassium clavulanate powder.
The water activity of a mixture is described in literature and is generally described to be in the range of 0.2 to 0.6 (optimum 0.4). It has been found surprisingly that the compressability of the mixture according to the present invention is excellent even with substantially low water activity of the mixture, namely  less than 0.2, which is a great advantage owing to the moisture sensitivity of e.g. potassium clavulanate. The water activity at 25xc2x0 C. of a amoxycillin trihydrate/potassium clavulanate mixture according to the present invention may be  less than 0.1, preferably  less than 0.05.
Mixtures of agglomerates of a xcex2-lactam antibiotic such as amoxicillin trihydrate with a second pharmaceutically active agent, e.g. potassium clavulanate, include particular preferred ranges in respect with average grain size and distribution of grain size, namely:
Average grain size of 100 xcexcm to 800 xcexcm, preferably 200 to 600 xcexcm, with the following distribution of grain size:
The bulk density of the mixture may, for example, be in the range of about 0.3 g/ml to about 0.8 g/ml, e.g. 0.3 g/ml to 0.8 g/ml; such as about 0.4 g/ml to about 0.6 g/ml; e.g. 0.4 g/ml to 0.6 g/ml. The angle of respose of the mixture which is a measure for flowability may be, e.g.  less than 40xc2x0, preferably  less than 35xc2x0.
Such mixtures are new and form also part of the present invention.
In another aspect the present invention provides a mixture of
agglomerates of an active xcex2-lactam, e.g. amoxycillin trihydrate, for example having an average grain size of 100 xcexcm to 800 xcexcm, for example 200 xcexcm to 600 xcexcm; and
a second active ingredient, e.g. a potassium salt of clavulanic acid, e.g. in form of a powder;
with or without auxiliaries;
the mixture having, for example, the following distribution of grain size:
xe2x80x83the mixture having
for example a bulk density of 0.3 g/ml to 0.8 g/ml, preferably 0.4 g/ml to 0.6 g/ml
for example an angel of repose of  less than 40xc2x0, preferably  less than 35xc2x0.
Mixtures of agglomerates of a xcex2-lactam antibiotic, for example amoxycillin trihydrate and a second pharmaceutically active agent, e.g. potassium clavulanate in form of a powder according to the present invention, containing optionally auxiliaries, may be directly compressed into tablets with high uniformity of the content of active ingredients and high uniformity of tablet weight, satisfactory mechanical stability and rapid release of active ingredient. Since no moisture is necessary in the entire production process of the tablets, potassium clavulanate is not degraded due to moisture effects which in addition ensures high stability of potassium clavulanate in the finished pharmaceutical preparation.
In another aspect, the present invention provides the use of auxiliary-free xcex2-lactam antibiotic agglomerates in the production of a mixture of a xcex2-lactam antibiotic; and a second pharmaceutically active agent, with or without auxiliaries, having for example an average grain size of 100 xcexcm to 800 xcexcm; and in a further aspect
Auxiliary-free agglomerates of xcex2-lactam antibiotics, especially of phenoxymethylpenicillin potassium, amoxicillin trihydrate and cephalexin monohydrate, which is suitable for direct tablet formation, characterised in that the agglomerates have an average volume-based grain size of 200-1000 xcexcm, preferably 400-600 xcexcm, with the following distribution of grain size:
and a bulk density of 0.4 to 0.8 g/ml; and in another aspect
A mixture suitable for direct tablet formation, which contains amoxycillin trihydrate and the potassium salt of clavulanic acid as the essential components, characterized in that amoxycillin trihydrate is present in the form of an agglomerate and the mixture has an average grain size of 100-800 xcexcm, preferably 200-600 xcexcm, with the following distribution of grain size:
and having a bulk density of 0.3 g/ml-0.8 g/ml, preferably 0.4 g/ml-0.6 g/ml, and an angle of repose of  less than 40xc2x0, preferably  less than 35xc2x0.
Tablets produced by compression of a mixture of agglomerates of a xcex2-lactam antibiotic, such as e.g. amoxicillin trihydrate with a second pharmaceutically active agent, e.g. potassium clavulanate and optionally with auxiliaries, may also be film-coated with film suspensions, dispersions (aqueous or organic solvents) in coating apparatus (drum, fluidized bed), for example as conventional.
Tablets, e.g. for oral administration comprising compressed agglomerates of a xcex2-lactam antibiotic, such as e.g. penicillin V potassium, amoxicillin trihydrate, cephalexin monohydrate optionally in mixture with pharmaceutically acceptable auxiliaries are new and form also part of the present invention.
In a further aspect the present invention provides a tablet for e.g. oral administration comprising compressed agglomerates of a xcex2-lactam antibiotic optionally in mixture with pharmaceutically acceptable auxiliaries.
Tablets, e.g. for oral administration, comprising compressed agglomerates of a xcex2-lactam antibiotic, such as e.g. amoxicillin trihydrate in mixture with a second pharmaceutically active agent, e.g. potassium clavulanate and optionally with pharmaceutically acceptable auxiliaries are new and form also part of the present invention.
In a further aspect the present invention provides a tablet, e.g. for oral administration comprising compressed agglomerates of a xcex2-lactam antibiotic, such as e.g. amoxicillin trihydrate in mixture with a second pharmaceutically active agent, e.g. potassium clavulanate and with or without pharmaceutically acceptable auxiliaries.